Genome‐wide analysis of adolescent psychotic‐like experiences shows genetic overlap with psychiatric disorders

Abstract

This study aimed to test for overlap in genetic influences between psychotic‐like experience traits shown by adolescents in the community, and clinically‐recognized psychiatric disorders in adulthood, specifically schizophrenia, bipolar disorder, and major depression. The full spectra of psychotic‐like experience domains, both in terms of their severity and type (positive, cognitive, and negative), were assessed using self‐ and parent‐ratings in three European community samples aged 15–19 years (Final N incl. siblings = 6,297–10,098). A mega‐genome‐wide association study (mega‐GWAS) for each psychotic‐like experience domain was performed. Single nucleotide polymorphism (SNP)‐heritability of each psychotic‐like experience domain was estimated using genomic‐relatedness‐based restricted maximum‐likelihood (GREML) and linkage disequilibrium‐ (LD‐) score regression. Genetic overlap between specific psychotic‐like experience domains and schizophrenia, bipolar disorder, and major depression was assessed using polygenic risk score (PRS) and LD‐score regression. GREML returned SNP‐heritability estimates of 3–9% for psychotic‐like experience trait domains, with higher estimates for less skewed traits (Anhedonia, Cognitive Disorganization) than for more skewed traits (Paranoia and Hallucinations, Parent‐rated Negative Symptoms). Mega‐GWAS analysis identified one genome‐wide significant association for Anhedonia within IDO2 but which did not replicate in an independent sample. PRS analysis revealed that the schizophrenia PRS significantly predicted all adolescent psychotic‐like experience trait domains (Paranoia and Hallucinations only in non‐zero scorers). The major depression PRS significantly predicted Anhedonia and Parent‐rated Negative Symptoms in adolescence. Psychotic‐like experiences during adolescence in the community show additive genetic effects and partly share genetic influences with clinically‐recognized psychiatric disorders, specifically schizophrenia and major depression.

Genetic association study of psychotic experiences in UK Biobank

“…A number of studies have demonstrated that psychopathology in the population is best described by a bifactor model with a common latent trait as well as specific traits, and that psychotic experiences index the more severe end of the common or shared trait 56,57 . Our findings of non-specificity of genetic risk for psychotic experiences with risk for other disorders are consistent with previous studies 7,8,11,12 . Nonetheless, despite lacking specificity, our results suggest that incorporating questions about frequency and, in particular, distress of psychotic experiences to self-reported assessments may allow a more valid identification of experiences that index schizophrenia and major mental health disorder liability.…”

“…Twin studies and genome-wide association studies (GWAS) have provided evidence that psychotic experiences are heritable (30-50% from twin studies 3-5 , 3-17% for SNP-heritability estimates 6,7 ), indicating that common genetic variants play a role in their aetiology. There have been three GWAS of psychotic experiences to date, all conducted in adolescent samples [7][8][9] with relatively small sample sizes (largest total sample n=10,098) and no reported genome-wide significant findings. These studies have focused on adolescence under the hypothesis that psychotic experiences at this age could be associated with an increased risk of mental health disorders in later life 10 .…”

“…Whilst there was an initial assumption that psychotic experiences in adolescence would specifically increase the risk for schizophrenia, evidence suggests a nonspecific increased risk for a broader psychopathology 10 , suggesting that research on psychotic experiences may have an important role in understanding the pathway to a wide array of clinical diagnoses 5 . However, to date no study has found strong evidence for association between genetic liabilities for schizophrenia or any other mental disorder with psychotic experiences 7,8,[11][12][13] .…”

Genetic and clinical analyses of psychosis spectrum symptoms in a large multi-ethnic youth cohort reveal significant link with ADHD

“…In the general population, however, the genetic etiology of psychotic symptoms across development is still largely unknown. The heritability of psychotic experiences has been estimated between 30-50% from twin studies (18,19) with the proportion of genetic variance explained by common variants (SNP-heritability) of 3-17% in adolescents (18,20). Adults with psychotic symptoms harbor increased genetic liability for a broad spectrum of psychiatric disorders, including schizophrenia and other neuropsychiatric disorders (21).…”

“…Adults with psychotic symptoms harbor increased genetic liability for a broad spectrum of psychiatric disorders, including schizophrenia and other neuropsychiatric disorders (21). While in adolescents some evidence suggests increased genetic risk for schizophrenia (and major depressive disorder) for specific features of psychosis (18), the reported effect sizes are very small, and these effects not very robust (22). In preadolescent youth, the relationship between genetic risk for psychiatric traits and psychotic symptoms has not yet been explored.…”